PROJECT SUMMARY The goal of the proposed study is to develop a platform for peptide-targeted delivery of therapeutics into myelin lesions in Multiple Sclerosis (MS) patients. MS is a chronic inflammatory disease that progressively destroys the protective myelin sheaths that encircle the axons in the central nervous system. Loss of myelin and oligodendrocytes, the myelin-forming cells in the CNS, impairs neuronal functions and leads to neurodegeneration. Current therapies target the immune response and can reduce frequency and severity of autoimmune attacks. However, there are no clinical therapies for repairing damaged myelin and stopping progressive neurodegenerative decline and patient disability. As research efforts identify novel strategies for myelin maintenance and repair, a recurring problem is how to deliver drugs or treatment agents to sites of myelin injury to achieve disease improvement. For example, inhibition of LINGO-1 (Leucine-Rich Repeat And Immunoglobulin Domain-Containing Protein 1) in vitro and in mouse MS animals improves maturation of oligodendrocyte progenitor cells and myelination, and treatments with humanized LINGO-1 antibodies are in clinical trials for optic neuritis. Systemic application to target lesions in brain, however, has limits as antibodies are diluted in the circulation, may have off-target effects elsewhere, and may not reach effective concentrations at lesion sites. We here propose to test a novel targeting approach for MS treatment in which we will use a unique tetrapeptide that selectively recognizes an epitope in injured but not uninjured myelin. The targeting peptide was identified in an in vivo phage display peptide library screen for penetrating brain injuries in the mouse, and targets to an extracellular matrix epitope selectively upregulated in injured myelin. We will test targeting specificity of the peptide to myelin lesions in mouse models of inflammatory demyelinating disease (EAE), and attempt to induce myelin repair and improve disease symptoms by selective targeting of Lingo-1 siRNA to myelin lesions through packaging the siRNA into peptide-coated nanoparticles for administration into the circulation. The peptide coat on the nanoparticle surface presents an address code to deliver the siRNA cargo through the open BBB specifically to the binding epitope at the lesion site where the siRNAi's are released from the non- coated particle core for target gene silencing during particle degradation. The development of peptide targeting technology for MS offers a new approach to beneficially modify disease through specific high local concentrations of disease modifying activity with reduced systemic effects. If successful, the proposed work will set the stage for developing peptide-targeting applications for a range of agents to MS lesions.